Inhibition of YAP function overcomes BRAF inhibitor resistance in melanoma cancer stem cells

Fisher, Mike; Grun, Daniel; Adhikary, Gautam; Xu, Wen; Eckert, Richard L.

doi:10.18632/oncotarget.22628

Cited by 69 publications

(76 citation statements)

References 38 publications

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“…Interestingly, a constitutively active construct NOTCH2‐NICD caused a higher increase in HEY1 expression than NOTCH1‐NICD in uveal melanoma cells . Alterations found in our study should be also considered in further research on melanoma cell response to drugs as both, Hippo and NOTCH pathways have been directly associated with resistance to inhibitors of the MAPK signaling pathway. A novel variant of FBXW7, V418M, that persists functional in melanoma cells, was identified in our study.…”

Section: Discussionmentioning

confidence: 56%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitindependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAF V600E ) and RAS subtypes, including NRAS Q61R and the rare HRAS Q61R variant, and additional alterations potentially leading to different ERK1/2 activity. Both RAS Q61R cell lines harbored a MEK1 P124S variant and exerted a low level of phospho-MEK1/2. Activity of the MAPK pathway was further attenuated in NRAS Q61R /MEK P124S cells by trametinib, and this effect was also shown in HRAS Q61R / MEK P124S melanoma cells. The observed variability in doubling time might be a consequence of diverse MAPK and PI3K/AKT pathway activities, but not exclusively, as a senescence program was also executed to different extent in distinct melanoma cell lines. Low percentages of senescent cells might result from mutations in CDKN2A, E2F3, and EZH2, and a high c-MYC expression. Vemurafenib and trametinib induced senescence concomitantly with c-MYC downregulation and irrespectively of CDKN2A mutation, but the EZH2 S412C variant might limit senescence induction. Damaging alterations in Hippo pathway-associated genes were accompanied with variability in the phosphorylation level of YAP1/TAZ and CTGF expression. Our study also suggests opposite activity of NOTCH2 F1209V and NOTCH2 N2002S variants. Additionally, we found a novel FBXW7 V418M variant that retained its function in melanoma cells. The obtained molecular data might be further exploited in genotype-phenotype relationship studies and in identifying novel biomarkers and therapies for melanomas.

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Section: Discussionmentioning

confidence: 56%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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“…YAP1 has been previously implicated in BRAFi resistance (4,(44)(45)(46)(47), so it is critical to understand whether ibrutinib is altering YAP1 activity. Transcriptionally inactive YAP1 is sequestered in the cytosol and upon various stimuli YAP1 can translocate into the nucleus where it modulates gene transcription.…”

Section: Ibrutinib Reduces the Nuclear Accumulation Of Yap1mentioning

confidence: 99%

“…Some phosphorylation events on YAP1 by LATS1/2 lead to inactivation and subsequent proteasomal degradation (42) whereas phosphorylation at other sites, targeted by YES1 and other kinases, is critical for YAP1 nuclear translocation and activation (43). YAP1 is activated in BRAFi-resistant melanoma cells and silencing or deletion of YAP1 reverses BRAFi resistance (4,(44)(45)(46)(47). In addition to melanoma, YAP1 has been implicated in many other cancer types including breast cancer (48), glioblastoma (49), pancreatic cancer (50), hepatocellular…”

mentioning

confidence: 99%

Ibrutinib blocks YAP1 activation and reverses BRAFi resistance in melanoma cells

Misek

Newbury

Chekalin

et al. 2020

Preprint

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Most BRAF-mutant melanoma tumors respond initially to BRAFi/MEKi therapy, although few patients have durable long-term responses to these agents. The goal of this study was to utilize an unbiased computational approach to identify inhibitors which reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we found that ibrutinib effectively reverses this signature and we demonstrate experimentally that ibrutinib re-sensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as a BTK inhibitor; however, neither BTK deletion nor treatment with acalabrutinib, another BTK inhibitor with reduced off-target activity, re-sensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib re-sensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple SRC kinase inhibitors. Since ibrutinib, but not acalabrutinib, has significant off-target activity against multiple SRC family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes either upregulated or downregulated by ibrutinib treatment are enriched in YAP1 target genes and we showed that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other SRC family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors.

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“…Therefore, activating Hippo pathway or inactivating YAP/TAZ has been regarded to be a potential way to repress cancer progression. For example, verteporfin, as an inhibitor of YAP, could attenuated the resistance of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitor in melanoma stem cells [5], and verteporfin could induce cell apoptosis in melanoma stem cells [6]. However, efforts in this direction are frustrated by the fact that the Hippo cascade is largely undruggable [7].…”

Section: Introductionmentioning

confidence: 99%

A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway

Bao

Yuan

et al. 2018

Cell Physiol Biochem

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Background/Aims: The roles and related mechanisms of RNA binding protein FUS (fused in sarcoma/translocated in liposarcoma) are unclear in numerous cancers, including hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription PCR (qRT-PCR), western blot, cell viability, transwell migration and invasion, tumor spheres formation and in vivo tumor formation assays were used to examine the effects of FUS on HCC progression in HuH7 and MHCC97 cells. Additionally, transcriptome analysis based on RNA-sequencing data, qRT-PCR, western blots, luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays were used to explore the LATS1/2 (large tumor suppressor kinases 1/2)-related mechanisms contributing to FUS functions. Finally, qRT-PCR and western blot analysis were used to detect the levels of FUS and LATS1/2 in HCC and adjacent normal tissues, and the correlation between them in HCC tissues. Results: Overexpression of FUS decreased cell viability, migration, invasion and stemness. Moreover, FUS interacted and stabilized LATS1/2 stability, and thus promoted LATS1/2 expression and activated Hippo pathway. Finally, FUS and LAST1/2 levels were positively correlated and significantly down-regulated in HCC tissues. Conclusion: We demonstrate that FUS/LATS1/2 axis inhibits HCC progression via activating Hippo pathway.

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Inhibition of YAP function overcomes BRAF inhibitor resistance in melanoma cancer stem cells

Cited by 69 publications

References 38 publications

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Ibrutinib blocks YAP1 activation and reverses BRAFi resistance in melanoma cells

A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway

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